Biodegradable vascular grafts

ABSTRACT

Disclosed herein are biodegradable scaffolds for in situ tissue engineering. In some examples, biodegradable vascular grafts and methods of fabricating and uses of such are disclosed. In some examples, a vascular graft includes a biodegradable scaffold including a biodegradable polyester tubular core, a biodegradable polyester electrospun outer sheath surrounding the biodegradable polyester tubular core and/or a thromboresistant agent, such as heparin, coating the biodegradable scaffold. The disclosed vascular grafts can be used for forming a blood vessel of less than 6 mm, including, but not limited to a coronary or peripheral arterial.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No. 14/365,987, filed Jun. 16, 2014, which is the § 371 U.S. National Stage of International Application No. PCT/US2012/071389, filed Dec. 21, 2012, which was published in English under PCT Article 21(2), which in turn claims the benefit of U.S. Provisional Application No. 61/579,585, filed Dec. 22, 2011, all of which applications are incorporated herein in their entirety.

ACKNOWLEDGMENT OF GOVERNMENT SUPPORT

This invention was made with government support under grant number HL089658 awarded by National Institutes of Health. The government has certain rights in the invention.

FIELD

This disclosure relates to biomaterials that promote tissue and organ regeneration and specifically to those that are biodegradable, such as biodegradable vascular grafts including a heparin-coated poly(glycerol sebacate)(PGS) scaffold with a poly(caprolactone) (PCL) sheath and methods of making and use thereof.

BACKGROUND

Small-diameter arterial substitutes are urgently needed as incidences of atherosclerotic arterial disease, especially coronary artery disease, rises with an aging population and increasing obesity. Autologous vessels are commonly used for bypass surgery to replace diseased and damaged arteries with an inner diameter less than 6 mm. However, autografts have several limitations including low availability, donor site morbidity, compliance mismatch, and late intimal hyperplasia, which often cause graft failure. Tissue engineering is an alternative to autografts with the potential to develop small-diameter arterial constructs that are nonthrombogenic, strong, and compliant. Yet, neither synthetic nor tissue-engineered grafts have yet to show clinical effectiveness in arteries smaller than 6 mm. Therefore, a need exists for small-diameter arterial substitutes that are nonthrombogenic, strong and compliant, but are effective in arteriers less than 6 mm.

SUMMARY

Host remodeling is important for the success of medical implants including vascular substitutes. A conceptual breakthrough in this disclosure is that properly designed scaffold made from rationally designed biomaterials can induce host tissue remodeling into a regeneration process. This bypasses the cell seeding and cell culture steps that are time consuming and costly, but are associated with typical tissue engineering strategies. This breakthrough is pivotal for translation of tissue engineering into practical utility in patient care. This concept is universally useful in many organs; the specific utility disclosed here is blood vessel, specifically artery.

Because artery is an elastic tissue an elastomer is used as a scaffold material. Chronic inflammation in response to the presence of foreign materials leads to fibrous encapsulation and scar tissue formation, thus to avoid scar and to regeneration artery, the specific materials of choice here were selected to degrade quickly. Furthermore, in some embodiments, to encourage host cell migration into the scaffold, a porous scaffold is used. It should be noted that this concept of matching mechanical property, proper porosity and appropriate degradation is applicable to other material and other tissues. This can serve as a guiding principle for inductive, in situ tissue engineering in vivo (i.e., tissue engineering without cell seeding prior to implantation).

Synthetic and tissue-engineered grafts have yet to show clinical effectiveness in arteries smaller than 6 mm. The inventors disclose herein cell-free biodegradable elastomeric grafts that degrade rapidly to yield neo-arteries nearly free of foreign materials 3 months after interposition grafting. This design focuses on enabling rapid host remodeling. Three months post-implantation, the neo-arteries resemble native arteries in the following aspects: regular, strong and synchronous pulsation, a confluent endothelium and contractile smooth muscle layers, co-expression of elastin, collagen and glycosaminoglycan, and tough and compliant mechanical properties. This cell-free approach represents a philosophical shift from the prevailing focus on cells in vascular tissue engineering, and may impact regenerative medicine in general.

As such, disclosed herein are biodegradable scaffolds, such as tissue engineering scaffolds, which can be used for the replacement and/or repair of damaged native tissues. In some embodiments, the disclosed scaffolds are included within a vascular graft. In some embodiments, a vascular graft includes a biodegradable scaffold comprising a biodegradable polymer tubular core. The biodegradable scaffold can further comprise a biodegradable polymer electrospun outer sheath surrounding the biodegradable polymer tubular core and/or a thromboresistant agent, such as heparin, coating the biodegradable scaffold. The disclosed vascular grafts can be used for forming a blood vessel of less than 6 mm, including, but not limited to a coronary or peripheral arterial.

Also disclosed are methods of fabricating a biodegradable scaffold and in particular a biodegradable vascular graft. In some embodiments, the method of fabricating a biodegradable vascular graft includes preparing a biodegradable poly(glycerol sebacate) (PGS) tubular core; surrounding the biodegradable polyester tubular core with a poly(caprolactone) (PCL) sheath; and coating an inner luminal surface of the biodegradable PGS tubular core with a thromboresistant agent, thereby forming a biodegradable vascular graft, in which at least 75% of the vascular graft degrades within 90 days of implantation in a subject.

The foregoing and other features and advantages of the disclosure will become more apparent from the following detailed description, which proceeds with reference to the accompanying figures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1I show the characterization of the composite graft and the overall scheme of its application. (FIG. 1A) Schematic representation of direct implantation of the cell-free graft and the proposed remodeling process of the graft into a biological neo-artery. (FIG. 1B) SEM images of the bi-layered structure of the PGS tubular core with PCL electrospun sheath, scale bar, 100 μm. Inset: top view of the graft. (FIG. 1C) Lumen of the PGS tube, scale bar, 100 μm. (FIG. 1D) The PCL fibrous sheath, scale bar, 10 μm. (FIG. 1E) Graft parameters as identified by micro-CT examination. (FIG. 1F) Suture retention test demonstrates that the sheath effectively improves the pull out strength of the graft. Suture pull out strength of the composite graft is higher than the break force (&) of 9-0 suture (n=5). p<0.05: * composite graft vs. 9-0 suture, ⁺ composite graft vs. rat aorta, # composite graft modulus (n=8) vs. that of the PGS tube (n=3). (FIG. 1G) Adsorption of heparin on PGS effectively reduces platelet adhesion as examined by lactate dehydrogenase assay (P<0.0001 between all groups). (FIG. 1H) Heparin adsorbs well on PGS surface to reduce fibrin formation. The few adhered platelets show quiescent morphology, scale bar, 10 μm. (FIG. 1I). Without heparin adsorption, significant amount of fibrin forms on PGS surfaces and the large number of adhered platelets exhibited activated morphology (circle), scale bar, 10 μm. Data represent mean±standard deviation for FIGS. 1E-1G.

FIGS. 2A-2D illustrate remodeling of the synthetic graft. (FIG. 2A) Gross appearance of the graft changed significantly upon host remodeling. Grafts redden, become translucent, and integrate well with host tissue over time. At 90 days, the grafted segment was covered by an adventitia-like tissue and completely integrated with the host tissue. Immunofluorescent staining of adventitial fibroblasts is available in FIGS. 11A-11C. Non-degradable sutures (black) marked the graft locations. (FIG. 2B) The burst pressure of the neo-artery (n=3) is statistically the same as native aorta (n=4). (FIG. 2C) Stress-strain curve of the neo-artery (day 90) resembles that of the native aorta and is much different from un-implanted grafts. (n=3). Bars represent standard error. (FIG. 2D) Compliance of the neo-artery at 90 days approaches that of native aorta (n=4). Standard errors for unimplanted grafts and PGS core are very small and barely visible at the plotted scale, n=3). Data represent mean±standard error for FIGS. 2B-2D.

FIGS. 3A-3D illustrate extensive smooth muscle cell infiltration occurs within 14 days. (FIG. 3A) Immuofluorescent staining of α-SMA demonstrated extensive smooth muscle cell presence within the remodeled graft wall. The tissue was split longitudinally, half of which is shown. Native aorta is on the right, its border with the graft is indicated by the dashed line, scale bar, 500 μm. L=lumen. (FIG. 3B) Magnified view of the mid-graft shows the presence of a mixed cell population with many α-SMA-negative cells. Nuclei counterstained by DAPI, scale bar, 250 μm. (FIG. 3C) Further magnification of the mid-graft indicates a complicated smooth muscle cell distribution, again suggesting an extensive but complicated remodeling process. Scale bar, 50 μm. (FIG. 3D) Co-staining of vWF and α-SMA merged with the bright-field image (darkened so as not to overwhelm the fluorescent images) indicates the smooth muscle layer is covered by an endothelialized lumen. Dark spots (*) in the bright-field image might be graft material. Scale bar, 100 μm. bright field images of original brightness are in FIG. 8.

FIGS. 4A-4H illustrate remodeling of the grafts. (FIG. 4A) H&E staining of the grafts indicate a transition into a neo-artery approaching the native aorta in structure with an apparent adventitia-like tissue. Immunofluorescent staining of adventitial fibroblasts is available in FIGS. 11A-11C. The vessel wall contains a very small amount of inflammatory cells by 90 days (*). The top of the 14-day sample was trimmed to remove the adjoining vein. Image merged from a panel of 100× micrographs, scale bar, 250 μm. (FIG. 4B) Magnified view to show the remodeling progress within the vessel wall. A substantial amount of ECM stains the vessel wall pink at 14 days. The ECM fibers are aligned circumferentially and the smooth muscle nuclei were elongated and aligned. 200×, scale bar, 50 μm. (FIG. 4C) Luminal area gradually increases with time and there is no statistical difference between the remodeled grafts and the native aorta, suggesting absence of aneurysm and stenosis. (FIG. 4D) CD68 staining of newly recruited macrophages shows the inflammatory response decreases over time and is largely resolved by 90 days. (FIG. 4E) The presence of CD163+ macrophages supports the constructive role of M2 macrophages during the remodeling of the grafts. (FIG. 4F) Total macrophage numbers decrease over time as with CD163+ macrophages, suggesting the remodeling process slows over time. (FIG. 4G) Smooth muscle cells stained with α-SMA are more organized as the grafts are remodeled over time. (FIG. 4H) Strong myosin heavy chain staining indicated contractile phenotype of the smooth muscle cells. All the immunofluorescent micrographs were 200×, with nuclei counterstained by DAPI, scale bar, 50 μm. Data represent mean±standard deviation for FIG. 4C and FIG. 4F.

FIGS. 5A-5B include histological images of the neo-artery revealed the presence and organization of major ECM components at 90 days. (FIG. 5A) The circumferential orientation of the ECM components in the neo-artery resembles that in native aorta. The neo-arteries have thicker vessel walls and contain more cells, suggesting the remodeling process is active, but the neo-artery bears no resemblance of a synthetic graft. Top: day 90 explant, bottom: native aorta. Verhoeff's, Masson's trichrome, and safranin-O staining revealed substantial amounts of elastin (black), collagen, and glycosaminoglycansin in the neo-artery. Elastin antibody stained elastic fibers that distributed throughout the neo-artery. Type I collagen was less dense in the neo-artery. However, its distribution is consistent with native aorta in that denser collagen I fibers populated the outer (adventitia) side of the vessel. Immunofluorescent staining of collagen III showed a wide distribution throughout the artery, as in native aorta. (FIG. 5B) Quantification of elastin (n=4) and total collagen (n=4) showed that neo-arteries contain 77% the elastin of the native aortas and the same amount of collagen. Data represent mean±standard deviation.

FIGS. 6A-6F show endothelialization of the neo-artery and vascular patency as examined at day 90. (FIG. 6A) Laser Doppler ultrasound imaging indicates excellent patency and regular synchronous pulsation with host aorta. (FIG. 6B) Angiography confirms the ultrasound examination and shows a patent lumen. Arrows indicate the graft location. (FIG. 6C) SEM of day 90 explant shows a smooth transition from host to neo-artery with a consistent diameter. Vessel split longitudinally, scale bar, 1 mm. Higher magnification micrographs show the endothelialization at the anastomosis (suture indicated by the arrowhead, scale bar, 10 μm) and mid-graft (scale bar, 1 μm). (FIG. 6D) vWF staining (red) demonstrates a confluent endothelium. Nuclei counterstained by DAPI (blue), scale bar, 250 μm. (FIG. 6E) Co-staining of vWF and α-SMA demonstrate that endothelial layer covers the lumen of the neo-artery and smooth muscle cells occupy the vessel wall, scale bar, 100 μm. (FIG. 6F) Transmission electron microscopy indicates a clear basement membrane (arrowheads) separating endothelial (EC) from smooth muscle cells (SMC), which correlates with the co-staining results of EC and SMC. Scale bar, 20 μm.

FIGS. 7A-7D illustrate heparin coating likely allows the grafts to maintain an open porous structure for cell infiltration at 3 days. (FIG. 7A) SEM shows that most of the pores in the graft were occupied, scale bar, 100 μm. (FIG. 7B) Higher magnification reveals that blood cells infiltrate into the pores. No distinguishable fibrin clot has been observed. Scale bar, 10 μm. (FIG. 7C) DAPI staining shows nucleated cells infiltrated into the grafts, scale bar, 250 μm. (FIG. 7D) H&E staining confirms infiltration of nucleated cells in the graft wall. Note that the cells in the lumen have flat elongated nuclei. Scale bar, 50 μm.

FIG. 8 are bright-field photomicrographs of unstained tissues indicate potential presence of graft materials (arrows). The amount of the putative graft remnants decreases rapidly and is mostly degraded by day 90. All images are 200×, scale bar, 50 μm, inset in 28-day image is 400×.

FIGS. 9A-9B illustrate neo-arteries have an adventitia-like outer layer populated by fibroblasts at 90 days. (FIG. 9A) Neo-arteries stain positive for fibroblast surface protein (FSP, red) in the outermost layer of the vessel wall. α-SMA co-stain (green) shows a clear boundary between fibroblast and smooth muscle populated layers, similar to that seen in the native aorta shown in (FIG. 9B). Scale bar: 100 μm.

FIGS. 10A-10D show examination of an occluded composite graft at 90 days post implantation. (FIG. 10A) Gross appearance of the occluded graft. (FIG. 10B) Cross-section of graft showed a collapsed lumen. Low magnification, scale bar: 500 μm. (FIG. 10C) H&E staining of occluded graft, scale bar: 200 μm. (FIG. 10D) Boxed region shows irregular cellular arrangement, and the graft appears largely unremodeled, scale bar: 50 μm.

FIGS. 11A-11C show PCL grafts are much more limited remodeling in 90 days. (FIG. 11A) Immunofluorescent staining indicates a thin layer of smooth muscle cells (α-SMA) near the graft lumen. Graft split longitudinally, image merged from 100× photomicrographs. (FIG. 11B) Co-staining of endothelial cells (vWF) and smooth muscle cells reveals an endothelial lining over the thin layer of smooth muscle. DAPI nuclei stain demonstrates penetration of nucleated cells in the graft wall. However the cells are not smooth muscle cells. 200×, scale bar, 50 μm. (FIG. 11C) Cross-sectional view of the graft confirms a thin smooth muscle layer near the lumen. Merged from 100× images, scale bar, 250 μm.

FIGS. 12A-12F show PCL grafts have limited remodeling in 90 days. (FIG. 12A) Graft is stiff and not integrated with host tissue as indicated by the clear distortion of the graft segment in the aorta. (FIG. 12B) Cross-sectional view of the graft shows layers of cells in the lumen and ablumen (outer surface). Nucleated cells are present within graft wall. (FIG. 12C) Verhoeff-van Gieson staining indicates the presence of small amounts of elastin (black). (FIG. 12D) A small amount of collagen III is visible near the lumen. (FIG. 12E) The expression of collagen I is the most extensive among the ECM proteins and spans the lumen to the ablumen. Collagen I deposition appears to be associated with nucleated cells in the graft wall. Coupling this with the “walled-off” appearance of the graft in H&E staining suggests that collagen I might serve to isolate the PCL from the host. (FIG. 12F) Elastin anti-body staining shows a low amount of elastin expression mostly near the lumen. All immunofluorescent images are 200×, scale bar, 50 μm.

DETAILED DESCRIPTION OF SEVERAL EMBODIMENTS I. Terms

Unless otherwise noted, technical terms are used according to conventional usage. Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The singular terms “a,” “an,” and “the” include plural referents unless context clearly indicates otherwise. Similarly, the word “or” is intended to include “and” unless the context clearly indicates otherwise. The term “comprises” means “includes.” The abbreviation, “e.g.” is derived from the Latin exempli gratia, and is used herein to indicate a non-limiting example. Thus, the abbreviation “e.g.” is synonymous with the term “for example.” Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, suitable methods and materials are described below. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

In order to facilitate review of the various embodiments of this disclosure, the following explanations of specific terms are provided:

Anticoagulant: A substance that prevents the clotting of blood (coagulation). Anticoagulants are commonly administered to subjects to prevent or treat thrombosis. Generally, anticoagulants are administered to treat or prevent deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, and mechanical prosthetic heart valves. Various types of anticoagulants with different mechanisms of action are available including anticoagulants that inhibit the effect of vitamin K (such as coumadin) or thrombin directly (such as argatroban, lepirudin, bivalirudin, and ximelagatran) or that activate antithrombin II that in turn blocks thrombin from clotting blood (such as heparin and derivative substances thereof).

Biocompatible: A term describing something that can be substantially non-toxic in the in vivo environment of its intended use, and is not substantially rejected by the patient's physiological system (e.g., is nonantigenic). This can be gauged by the ability of a material to pass the biocompatibility tests set forth in International Standards Organization (ISO) Standard No. 10993 and/or the U.S. Pharmacopeia (USP) 23 and/or the U.S. Food and Drug Administration (FDA) blue book memorandum No. G95-1, entitled “Use of International Standard ISO-10993, Biological Evaluation of Medical Devices Part-1: Evaluation and Testing.” Typically, these tests measure a material's toxicity, infectivity, pyrogenicity, irritation potential, reactivity, hemolytic activity, carcinogenicity and/or immunogenicity. A biocompatible structure or material, when introduced into a majority of subjects, will not cause a significantly adverse reaction or response. Furthermore, biocompatibility can be affected by other contaminants such as prions, surfactants, oligonucleotides, and other agents or contaminants. The term “biocompatible material” refers to a material that does not cause toxic or injurious effects on a tissue, organ, or graft.

Biodegradable polymer: A polymer that can be cleaved either enzymatically or hydrolytically to break it down sufficiently so as to allow the body to absorb or clear it away. A biodegradable graft is a graft in which at least a significant portion (such as at least 50%) of the graft degrades within one year of implantation.

Cell-free graft: A graft which does not contain cells, such as, endothelial or smooth muscle cells at the time of implantation.

Coat: As used herein “coating”, “coatings”, “coated” and “coat” are forms of the same term defining material and process for making a material where a first substance or substrate surface is at least partially covered or associated with a second substance. Both the first and second substance are not required to be different. Further, when a surface is “coated” as used herein, the coating may be effectuated by any chemical or mechanical bond or force, including linking agents. The “coating” need not be complete or cover the entire surface of the first substance to be “coated”. The “coating” may be complete as well (e.g., approximately covering the entire first substance). There can be multiple coatings and multiple substances within each coating. The coating may vary in thickness or the coating thickness may be substantially uniform. Coatings contemplated in accordance with the present disclosure include, but not limited to medicated coatings, drug-eluting coatings, drugs or other compounds, pharmaceutically acceptable carriers and combinations thereof, or any other organic, inorganic or organic/inorganic hybrid materials. In an example, the coating is a thromboresistant coating which has anticoagulant properties, such as heparin.

Electrospinning: A process in which fibers are formed from a solution or melt by streaming an electrically charged solution or melt through an orifice.

Poly(caprolactone)(PCL): A biodegradable polyester with a low melting point of around 60° C. and a glass transition temperature of about −60° C. PCL is prepared by ring opening polymerization of ε-caprolactone using a catalyst such as stannous octoate. PCL is degraded by hydrolysis of its ester linkages in physiological conditions (such as in the human body) and can be used as an implantable biomaterial. In some example, PCL is used as a sheath around a PGS scaffold.

Poly(glycerol sebacate)(PGS): An elastomeric biodegradable polyester. In some examples, a disclosed vascular graft includes a PGS scaffold.

Scaffold: A structural support facilitating cell infiltration and attachment in order to guide vessel growth. As disclosed herein, a biodegradable scaffold can be used to form a vascular graft. In some examples, a biodegradable scaffold includes a biodegradable polyester tubular core and a biodegradable polyester electrospun outer sheath surrounding the biodegradable polyester tubular core.

Sheath: An outer coating surrounding either partially or completely an inner layer. As disclosed herein, a sheath surrounds either partially or completely the biodegradable polyester tubular core of a disclosed vascular graft.

Subject: Living multi-cellular vertebrate organisms, a category that includes human and non-human mammals (such as laboratory or veterinary subjects). In an example, a subject is a human. In an additional example, a subject is selected that is in need of an implant for damaged or defective neo-artery.

Vascular graft: A tubular member which acts as an artificial vessel. A vascular graft can include a single material, a blend of materials, a weave, a laminate or a composite of two or more materials.

II. Biodegradable Scaffolds

Disclosed herein are scaffolds, such as tissue engineering scaffolds, including for the replacement and/or repair of damaged native tissues. Although the present disclosure illustrates in detail the use of a disclosed scaffold within a vascular graft, it is contemplated that a disclosed scaffold can be utilized for additional in situ tissue engineering applications, including, but not limited to bone, intestine, liver, lung, or any tissue with sufficient progenitor/stem cells. In some examples, a scaffold is biodegradable and/or biocompatible and includes a biodegradable core, such as a biodegradable polyester tubular core for a vascular graft. In some examples, the biodegradable polyester tubular core includes PGS. In some examples, the biodegradable polyester tubular core includes PGS and one or more biodegradable substances similar to PGS, such as a polymer or an elastomer with relatively fast degradation rate (as described in detail below). These may include derivatives of polyglycolic acid, polycarbonate, polyurethane, polyethylene glycol, and poly(orthoester). It is contemplated that a disclosed graft may include PGS or any biodegradable and/or biocompatible substance with similar degradation rates and elasticity of PGS. In some examples, a disclosed scaffold includes PGS and/or one or more of the following polymers: polylactides (PLAs), poly(lactide-co-glycolides) (PLGAs), poly(dioxanone), polyphosphazenes, polyphosphoesters (such as, poly[1,4-bis(hydroxyethyl)terephthalate-alt-ethyloxyphosphate]; poly[1,4-bis(hydroxyethyl)terephthalate-alt-ethyloxyphosphate]-co-1,4-bis(hydroxyethyl)terephthalate-co-terephthalate; poly[(lactide-co-ethylene glycol)-co-ethyloxyphosphate]); polycaprolactone; poly(urethanes), polyglycolides (PGA), polyanhydrides, and polyorthoesters or any other similar synthetic polymers that may be developed that are biologically compatible. The term “biologically compatible, synthetic polymers” shall also include copolymers and blends, and any other combinations of the forgoing either together or with other polymers generally. The use of these polymers will depend on given applications and specifications required. A more detailed discussion of these polymers and types of polymers is set forth in Brannon-Peppas, Lisa, “Polymers in Controlled Drug Delivery,” Medical Plastics and Biomaterials, November 1997, which is incorporated by reference as if set forth fully herein.

In some embodiments, grafts, such as vascular grafts, which are biodegradable and/or biocompatible are disclosed. For example, a vascular graft can include a disclosed biodegradable scaffold with a biodegradable polyester core, such as a biodegradable polyester tubular core for a vascular graft. In some examples, the biodegradable polyester tubular core includes PGS. In some examples, the biodegradable polyester tubular core includes PGS and one or more biodegradable substances similar to PGS, such as a polymer or an elastomer with relatively fast degradation rate (as disclosed herein). These may include derivatives of polyglycolic acid, polycarbonate, polyurethane, polyethylene glycol, and poly(orthoester).

In some examples, a disclosed scaffold/graft includes one or more natural polymers including, but are not limited to amino acids, peptides, denatured peptides such as gelatin from denatured collagen, polypeptides, proteins, carbohydrates, lipids, nucleic acids, glycoproteins, minerals, lipoproteins, glycolipids, glycosaminoglycans, and proteoglycans. In certain embodiments, collagen is included. In certain embodiments, collagen is excluded. In certain cases, non-living macromolecular structures derived from biological tissues including, but are not limited to skins, vessels, intestines, internal organs, can be used alone or in combination with synthetic polymers named above.

In some examples, the scaffold or graft includes pores to facilitate cell infiltration, but pores are not necessarily required. In examples in which pores are built into the scaffolds or grafts, the pore size can range from 2 to 500 microns (μm). In some examples, the biodegradable polyester core, such as a biodegradable polyester tubular core, comprises pores of about 1 μm to about 500 μm, from about 10 μm to about 400 μm, about 20 μm to about 300 μm, about 1 μm to about 10 μm, about 3 μm to about 7 μm, such as 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, 10 μm, 11 μm, 12 μm, 13 μm, 14 μm, 15 μm, 16 μm, 17 μm, 18 μm, 19 μm, 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm, 150 μm, 200 μm, 250 μm, 300 μm, 350 μm, 400 μm, 450 μm, or 500 μm. In some examples, pores are about 20 μm to about 30 μm, including about 20 μm, 21 μm, 22 μm, 23 μm, 24 μm, 25 μm, 26 μm, 27 μm, 28 μm, 29 μm, and 30 μm. In some examples, the pores are uniformly distributed. In some examples, the pores are non-uniformly distributed. In some examples, the biodegradable polyester tubular porous core has at least 75% pore interconnectivity, such as about 80% to about 90%, about 90% to about 98%, including 75%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.99% interconnectivity.

In some examples, the biodegradable scaffold further includes a sheath which surrounds the biodegradable polyester tubular core. In some examples, the sheath is a biodegradable polyester electrospun sheath which surrounds the biodegradable polyester tubular core to prevent, inhibit or reduce bleeding from such graft. In some examples, the biodegradable polyester electrospun sheath includes PCL or a PCL like substance which is capable of forming a leak-proof sheath around the biodegradable polyester electrospun sheath. In some examples, a biodegradable scaffold does not include a sheath. For example, a biodegradable scaffold includes one or more biodegradable polyesters or like substances without a sheath. In one particular example, a biodegradable scaffold includes PGS and one or more carrier polymers, such as such as poly(lactic acid) (PLA), polycaprolactone (PCL) or poly(glycolic acid) (PGA), and/or the copolymer poly(lactide-co-glycolide) (PLGA).

In one particular example, the biodegradable scaffold includes a PGS core surrounded by an electrospun PCL sheath.

In some examples, the sheath has a thickness between about 5 m and 30 μm, such as between about 10 μm and about 20 μm, including 10 μm, 11 μm, 12 μm, 13 μm, 14 μm, 15 μm, 16 μm, 17 μm, 18 μm, 19 μm, 20 μm, 21 μm, 22 μm, 23 μm, 24 μm, 25 μm, 26 μm, 27 μm, 28 μm, 29 μm, and 30 μm. In one example, the biodegradable polyester electrospun outer sheath has a thickness of about 15 μm.

In some examples, the biodegradable scaffold is coated with a biocompatible and/or biodegradable material. It is contemplated that one of ordinary skill in the art can determine with but limited experimentation, which substrates are suitable for a particular application. In some examples, the inner luminal surface of the biodegradable scaffold is coated with a biocompatible and/or biodegradable material. It is contemplated that such coating may be complete or partial. In some examples, the inner luminal surface of a biodegradable scaffold is coated completely with a thromboresistant agent, such as heparin and/or other compounds known to one of skill in the art to have similar anti-coagulant properties as heparin, to prevent, inhibit or reduce clotting within the inner lumen of the vascular graft.

In some examples, the scaffold can be impregnated with any of a variety of agents, such as, for example, suitable growth factors, stem cell factor (SCF), vascular endothelial growth factor (VEGF), transforming growth factor (TGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), cartilage growth factor (CGF), nerve growth factor (NGF), hepatocyte growth factor (HGF), stromal cell derived factor (SDF), platelet derived growth factor (PDGF), keratinocyte growth factor (KGF), skeletal growth factor (SGF), osteoblast-derived growth factor (BDGF), insulin-like growth factor (IGF), cytokine growth factor (CGF), stem cell factor (SCF), colony stimulating factor (CSF), growth differentiation factor (GDF), integrin modulating factor (IMF), calmodulin (CaM), thymidine kinase (TK), tumor necrosis factor (TNF), growth hormone (GH), bone morphogenic proteins (BMP), interferon, interleukins, cytokines, integrin, collagen, elastin, fibrillins, fibronectin, laminin, glycosaminoglycans, heparan sulfate, chondrotin sulfate (CS), hyaluronic acid (HA), vitronectin, proteoglycans, transferrin, cytotactin, tenascin, and lymphokines.

The various dimensions of a disclosed scaffold or graft may vary according to the desired use. In principle, the dimensions will be similar to those of the host tissue in which the scaffold/graft is being used to replace. For examples, the inner diameter of a vascular graft will match that of the host vessel to be replaced. In some examples, the inner diameter is between about 1 mm to 5 mm. In some examples, a disclosed vascular graft has an inner diameter of between about 700 μm to about 5000 μm, such as about 710 μm to about 4000 μm, such as about 720 μm to about 3000 μm, such as about 1000 μm to about 5000 μm, including 710 μm, 711 μm, 712 μm, 713 μm, 714 μm, 715 μm, 716 μm, 717 μm, 718 μm, 719 μm, 720 μm, 721 μm, 722 μm, 723 μm, 724 μm, 725 μm, 726 μm, 727 μm, 728 μm, 729 μm, 730 μm, 731 μm, 732 μm, 733 μm, 734 μm, 735 μm, 736 μm, 737 μm, 738 μm, 739 μm, 740 μm, 741 μm, 742 μm, 743 μm, 744 μm, 745 μm, 746 μm, 747 μm, 748 μm, 749 μm, 750 μm, 800 μm, 850 μm, 900 μm, 950 μm, 1000 μm, 2000 μm, 3000 μm, 4000 μm or 5000 μm. In some examples, the inner diameter of a disclosed vascular graft is about 720 μm. In some examples, the inner diameter of a disclosed vascular graft is about 1000 μm. In some examples, the inner diameter of a disclosed vascular graft is about 2000 μm. In some examples, the inner diameter of a disclosed vascular graft is about 3000 μm.

Typically, the wall thickness of a disclosed scaffold or vascular graft is designed to match that of the host tissue or vessel to be replaced. However, it is contemplated the graft can be thicker or thinner, if desired. In some examples, a disclosed vascular graft has a wall thickness between about 100 μm and about 500 μm, such as about 150 μm and about 450 μm, including about 200 μm and about 400 μm, such as about 100 μm, 125 μm, 150 μm, 175 μm, 200 μm, 225 μm, 250 μm, 275 μm, 300 μm, 325 μm, 350 μm, 375 μm, 400 μm, 425 μm, 450 μm, 475 μm, or 500 μm. In some examples, a disclosed vascular graft has a wall thickness between about 270 μm and about 300 μm, such as about 285 μm and about 295 μm, including 270 μm, 271 μm, 272 μm, 273 μm, 274 μm, 275 μm, 276 μm, 277 μm, 278 μm, 279 μm, 280 μm, 281 μm, 282 μm, 283 μm, 284 μm, 285 μm, 286 μm, 287 μm, 288 μm, 289 μm, 290 μm, 291 μm, 292 μm, 293 μm, 294 μm, 295 μm, 296 μm, 297 μm, 298 μm, 299 μm, or 300 μm. In some examples, the wall thickness is about 290 μm.

In some examples, at least 50%, such as about 55% to about 70%, about 80% to about 90%, about 90% to about 98%, including 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.99% of a disclosed scaffold/graft, such as a disclosed vascular graft, degrades within one year of implantation, such as within 1 to 10 months, including within 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months or 12 months of implantation. In some examples, at least 50%, such as about 55% to about 70%, about 80% to about 90%, about 90% to about 98%, including 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.99% of a disclosed scaffold/graft, such as a disclosed vascular graft, degrades within 2 weeks to 52 weeks of implantation, including within 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, 26 weeks, 28 weeks, 30 weeks, 32 weeks, 34 weeks, 36 weeks, 38 weeks, 40 weeks, 42 weeks, 44 weeks, 46 weeks, 48 weeks, 50 weeks, or 52 weeks of implantation.

In some examples, about 80% to about 95% of the graft degrades within 4 weeks. In some examples, about 80% to about 95% of the graft degrades within 6 weeks. In some examples, about 80% to about 95% of the graft degrades within 8 weeks. In some examples, about 80% to about 95% of the graft degrades within 10 weeks. In some examples, about 80% to about 95% of the graft degrades within 14 weeks. In some examples, about 80% to about 95% of the graft degrades within 16 weeks. In some examples, about 80% to about 95% of the graft degrades within 18 weeks. In some examples, about 80% to about 95% of the graft degrades within 20 weeks. In some examples, about 80% to about 95% of the graft degrades within 22 weeks. In some examples, about 80% to about 95% of the graft degrades within 24 weeks. In some examples, about 80% to about 95% of the graft degrades within 26 weeks.

In some examples, at least 90% of the graft degrades within 4 weeks. In some examples, at least 90% of the graft degrades within 6 weeks. In some examples, at least 90% of the graft degrades within 8 weeks. In some examples, at least 90% of the graft degrades within 10 weeks. In some examples, at least 90% of the graft degrades within 12 weeks. In some examples, at least 90% of the graft degrades within 14 weeks. In some examples, at least 90% of the graft degrades within 16 weeks. In some examples, at least 90% of the graft degrades within 18 weeks. In some examples, at least 90% of the graft degrades within 20 weeks. In some examples, at least 90% of the graft degrades within 22 weeks. In some examples, at least 90% of the graft degrades within 24 weeks. In some examples, at least 90% of the graft degrades within 26 weeks.

In some examples, at least 95% of the graft degrades within 4 weeks. In some examples, at least 95% of the graft degrades within 6 weeks. In some examples, at least 95% of the graft degrades within 8 weeks. In some examples, at least 95% of the graft degrades within 10 weeks. In some examples, at least 95% of the graft degrades within 12 weeks. In some examples, at least 95% of the graft degrades within 14 weeks. In some examples, at least 95% of the graft degrades within 16 weeks. In some examples, at least 95% of the graft degrades within 18 weeks. In some examples, at least 95% of the graft degrades within 20 weeks. In some examples, at least 95% of the graft degrades within 22 weeks. In some examples, at least 95% of the graft degrades within 24 weeks. In some examples, at least 95% of the graft degrades within 26 weeks.

In some examples, at least 50%, such as about 55% to about 70%, about 80% to about 90%, about 90% to about 98%, including 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.99% of a disclosed scaffold/graft, such as a disclosed vascular graft, degrades within 4 weeks of implantation, such as within 1 week, 2 weeks, 3 weeks and 4 weeks.

In some examples, a disclosed scaffold/graft, such as a disclosed vascular graft, is cell-free, in which it does not include any living cells, such as smooth muscle cells or endothelial cells.

III. Methods of Fabrication

Also disclosed herein are methods of fabricating a scaffold or graft, such as a vascular graft. A disclosed scaffold or graft may be fabricated by methods known to those of skill in the art. In some embodiments, a method of fabricating a scaffold or graft, such as a vascular graft, which is biodegradable and/or biocompatible comprises preparing a biodegradable polyester core (such as a tubular core for a vascular graft) and surrounding the biodegradable polyester core with a sheath. In some examples, a disclosed scaffold or graft is prepared by using salt fusion and leaching or electroprocessing, such as electrospinning. In particular examples, the method includes synthesizing the biodegradable polyester material and then forming a core, such as a tubular core, with such material. The biodegradable polyester material can be synthesized by any method known to one of skill in the art to generate the material with desired properties, including, but not limited to, a desired shape, thickness, porosity, fiber strength, or elasticity. For example, PGS can be first synthesized by any method known to one of ordinary skill in the art, including, but not limited to, the method described in Wang et al. (Nat. Biotechnol. 20:602-606, 2002) which is hereby incorporated by reference in its entirety). The synthesized biocompatible and biodegradable polyester material can then formed into the desired shape by use of any method known to one of ordinary skill in the art. In some examples, the biodegradable and biocompatible polyester material is shaped based upon the shape of the structure, such as a blood vessel, the resulting vascular graft is replacing. In some examples, a PGS tube is formed by the method described in Lee et al. (Proc Natl Acad Sci USA 108: 2705-2710, 2011) which is hereby incorporated by reference in its entirety except that a 1 mm mandrel and a 1.25 mm outer mold is used.

In some examples, the biodegradable scaffold or biodegradable core, such as tubular core, is fabricated to comprise pores of about 1 μm to about 500 μm, from about 10 μm to about 300 μm, about 20 μm to about 300 μm, about 1 μm to about 10 μm, about 3 μm to about 7 μm, such as 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, 10 μm, 11 μm, 12 μm, 13 μm, 14 μm, 15 μm, 16 μm, 17 μm, 18 μm, 19 μm, 20 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm, 150 μm, 200 μm, 250 μm, 300 μm, 350 μm, 400 μm, 450 μm, or 500 μm. In some examples, pores are about 20 μm to about 30 μm, including about 20 μm, 21 μm, 22 μm, 23 μm, 24 μm, 25 μm, 26 μm, 27 μm, 28 μm, 29 μm, and 30 μm. In some examples, the biodegradable scaffold or core is fabricated to include uniformly distributed pores. In some examples, the biodegradable polyester scaffold or core is fabricated to include non-uniformly distributed pores. In some examples, the biodegradable scaffold is fabricated to not include pores.

In some examples, the biodegradable polyester tubular porous core is fabricated to include at least 75% pore interconnectivity, such as about 80% to about 90%, about 90% to about 98%, including 75%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.99% interconnectivity.

In some examples, sheath is fabricated to surround the biodegradable polyester core, such as tubular core, by electrospinning. For example, a PCL sheath is formed around a PGS or like composition core by electrospinning PCL onto a PGS core, such as PGS-salt template (as described in the Examples below). In some examples, the sheath is fabricated to have a thickness between about 5 μm and 30 μm, such as between about 10 μm and about 20 μm, including 10 μm, 11 μm, 12 μm, 13 μm, 14 μm, 15 μm, 16 μm, 17 μm, 18 μm, 19 μm, 20 μm, 21 μm, 22 μm, 23 μm, 24 μm, 25 μm, 26 μm, 27 μm, 28 μm, 29 μm, and 30 μm. In one example, the biodegradable polyester electrospun outer sheath has a thickness of about 15 μm.

In further examples, the disclosed methods of fabrication include coating a surface of the biodegradable scaffold, such as a surface of a biodegradable polyester tubular core with a biocompatible and/or biodegradable material. It is contemplated that one of ordinary skill in the art can determine with but limited experimentation, which substrates are suitable for a particular application. In some examples, the inner luminal surface of the biodegradable scaffold is coated with a biocompatible and/or biodegradable material. It is contemplated that such coating may be complete or partial. In some examples, the inner luminal surface of a biodegradable scaffold is coated completely with a thromboresistant agent, such as heparin and/or other compounds known to one of skill in the art to have similar anti-coagulant properties as heparin, to prevent, inhibit or reduce clotting within the inner lumen of the vascular graft.

The various dimensions of a disclosed graft may vary according to the desired use. In some examples, the method of fabrication is performed to generate a vascular graft with an inner diameter which matches that of the host vessel to be replaced. In some examples, the inner diameter is between about 1 mm to 5 mm. In some examples, a disclosed vascular graft has an inner diameter of between about 700 μm to about 5000 μm, such as about 710 μm to about 4000 μm, such as about 720 μm to about 3000 μm, such as about 1000 μm to about 5000 μm, including 710 μm, 711 μm, 712 μm, 713 μm, 714 μm, 715 μm, 716 μm, 717 μm, 718 μm, 719 μm, 720 μm, 721 μm, 722 μm, 723 μm, 724 μm, 725 μm, 726 μm, 727 μm, 728 μm, 729 μm, 730 μm, 731 μm, 732 μm, 733 μm, 734 μm, 735 μm, 736 μm, 737 μm, 738 μm, 739 μm, 740 μm, 741 μm, 742 μm, 743 μm, 744 μm, 745 μm, 746 μm, 747 μm, 748 μm, 749 μm, 750 μm, 800 μm, 850 μm, 900 μm, 950 μm, 1000 μm, 2000 μm, 3000 μm, 4000 μm or 5000 μm. In some examples, the inner diameter of a disclosed vascular graft is fabricated to be about 720 μm. In some examples, the inner diameter of a disclosed vascular graft is fabricated to be about 1000 μm. In some examples, the inner diameter of a disclosed vascular graft is about fabricated to be about 2000 μm. In some examples, the inner diameter of a disclosed vascular graft is fabricated to be about 3000 μm.

In some examples, the method of fabrication is performed to generate a vascular graft with a wall thickness which matches that of the host vessel to be replaced. However, it is contemplated the graft wall can be fabricated with a thicker or thinner wall than that which is being replaced, if desired. In some examples, a disclosed vascular graft is fabricated to have a wall thickness between about 100 μm and about 500 μm, such as about 150 μm and about 450 μm, including about about 200 μm and about 400 μm, such as about 100 μm, 125 μm, 150 μm, 175 μm, 200 μm, 225 μm, 250 μm, 275 μm, 300 μm, 325 μm, 350 μm, 375 μm, 400 μm, 425 μm, 450 μm, 475 μm, or 500 μm. In some examples, a disclosed vascular graft is fabricated to have a wall thickness between about 270 μm and about 300 μm, such as about 285 μm and about 295 μm, including 270 μm, 271 μm, 272 μm, 273 μm, 274 μm, 275 μm, 276 μm, 277 μm, 278 μm, 279 μm, 280 μm, 281 μm, 282 μm, 283 μm, 284 μm, 285 μm, 286 μm, 287 μm, 288 μm, 289 μm, 290 μm, 291 μm, 292 μm, 293 μm, 294 μm, 295 μm, 296 μm, 297 μm, 298 μm, 299 μm, or 300 μm. In some examples, the wall thickness is about 290 μm.

In some examples, the method of fabrication are performed to generate a scaffold/graft such as a vascular graft that at least 50%, such as about 55% to about 70%, about 80% to about 90%, about 90% to about 98%, including 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or 99.99% of such scaffold/graft degrades within one year of implantation, such as within one three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months or twelve months.

In some examples, the method of fabrication includes generating a cell-free scaffold/graft, such as a cell-free vascular graft, in which the graft does not include any living cells, such as smooth muscle cells or endothelial cells.

IV. Methods of Use

It is contemplated that the disclosed scaffolds/grafts can be used to guide host tissue remodeling in many different tissues, including any tissue that has progenitor cells. The disclosed biodegradable scaffolds can be used to facilitate tissue regeneration in vivo by providing a structural frame for which tissue regeneration can occur. In some examples, the scaffolds/grafts or constructed to allow and facilitate the infiltration of host cells including progenitor cells. In some examples, the scaffolds/graft allows and facilitates host remodeling of the biodegradable structure, so that eventually the polymeric structure is replaced by the desirable host tissue. It is contemplated that the methods of fabrication disclosed in Section III and the Examples below can be modified as desired by one of ordinary skill in the art to fabricate a graft with the appropriate dimensions and features depending upon tissue which is to be replaced.

The disclosed scaffolds are especially useful for applications in soft and elastomeric tissues. In some particular examples, the generated tissue constructs are for the replacement and/or repair of damaged native tissues. For example, the disclosed constructs are contemplated to be implantable for tensile load bearing applications, such as being formed into tubes and implanted as artery interpositional grafts as well as other tensile load bearing applications. A disclosed scaffold/graft can be utilized for additional in situ tissue engineering applications, including, but not limited to bone, intestine, liver, lung, or any tissue with sufficient progenitor/stem cells. For example, uses can range from sheets for hernia repair, prolapse, and wound dressings, to complex tubes for blood vessel, nerve and trachea repair. Additionally, aligned random transition spinning may be useful for ligament-bone interfaces.

In some particular examples, a biodegradable scaffold comprising a biodegradable polyester core and a biodegradable polyester electrospun outer sheath surrounding the biodegradable polyester core with or without a thromboresistant agent coating the biodegradable scaffold is used to facilitate tissue regeneration in vivo by providing a structural frame for which tissue regeneration can occur.

In some examples, a disclosed vascular graft is used to form a blood vessel in vivo. For example, a disclosed vascular graft can be implanted into a subject in need of vascular graft at the desired location to form a conduit in which blood may initial flow and ultimately form a blood vessel, such as blood vessel of less than 10 mm, such as less than 6 mm or less than 4 mm, including, about 9 mm, about 8 mm, about 7 mm, about 6 mm, about 5 mm, about 4 mm, about 3 mm, about 2 mm, or about 1 mm, or as low as 0.5 mm. In some examples, the vascular graft is used as a coronary or a peripheral arterial graft or venous grafts or lymphatic vessels. In some examples, the vascular graft is used as an arteriovenous shunt for dialysis access where “maturation” of 2-3 months is common.

The following examples are provided to illustrate certain particular features and/or embodiments. These examples should not be construed to limit the disclosure to the particular features or embodiments described. 

We claim:
 1. A vascular graft, comprising: a biodegradable scaffold comprising a biodegradable polyester tubular core comprising poly(glycerol sebacate) (PGS) and having small pores of about 1 μm to about 500 μm and comprising an inner lumen surface and an outer surface; and a biodegradable polyester electrospun outer sheath surrounding the outer surface of the biodegradable polyester tubular core; and wherein the vascular graft is cell-free.
 2. The vascular graft of claim 1, wherein the biodegradable polyester tubular core comprises a copolymer comprising the poly(glycerol sebacate) (PGS).
 3. The vascular graft of claim 1, wherein the biodegradable polyester tubular core consists essentially of the PGS.
 4. The vascular graft of claim 1, wherein the biodegradable polyester electrospun sheath comprises poly(caprolactone) (PCL).
 5. The vascular graft of claim 1, further comprising a thromboresistant agent coating the biodegradable scaffold.
 6. The vascular graft of claim 1, wherein the thromboresistant agent comprises heparin.
 7. The vascular graft of claim 1, wherein the thromboresistant agent coats the inner lumen surface of the biodegradable polyester tubular core.
 8. The vascular graft of claim 1, wherein at least 75% of the pores are interconnected.
 9. The vascular graft of claim 1, wherein at least 95% of the pores are interconnected.
 10. The vascular graft of claim 1, wherein at least 99% of the pores are interconnected.
 11. The vascular graft of claim 1, wherein the vascular graft has an inner diameter of between 700 μm to
 5000. 12. The vascular graft of claim 1, wherein the vascular graft has a wall thickness between 100 μm and 500 μm.
 13. The vascular graft of claim 1, wherein the biodegradable polyester electrospun outer sheath has a thickness between 5 μm and 30 μm.
 14. The vascular graft of claim 1, wherein at least 95% of the vascular graft degrades within 90 days of implantation.
 15. The vascular graft of claim 1, wherein the vascular graft is used for forming a blood vessel of less than 6 mm.
 16. The vascular graft of claim 15, wherein the vascular graft is used for forming a blood vessel of less than 4 mm.
 17. The vascular graft of claim 1, wherein the vascular graft is used as a coronary or a peripheral arterial graft.
 18. A method of forming a blood vessel in a subject, comprising: implanting the vascular graft of claim 1 into a subject at a target location to form a conduit in which blood flows through the vascular graft.
 19. A method of fabricating a vascular graft, comprising: preparing a biodegradable polyester tubular core comprising poly(glycerol sebacate) (PGS) and having small pores of about 1 μm to about 500 μm and comprising an inner lumen surface and an outer surface; surrounding the outer surface of the biodegradable polyester tubular core with a biodegradable polyester electrospun outer sheath; and coating the inner luminal surface of the biodegradable polyester tubular core with a thromboresistant agent, thereby forming a biodegradable vascular graft, in which at least 75% of the vascular graft degrades within 90 days of implantation in a subject.
 20. A biodegradable scaffold that induces tissue regeneration without cell seeding of the scaffold prior to implantation into a subject's body, wherein the scaffold comprises a biodegradable polyester core comprising poly(glycerol sebacate) (PGS) and having small pores of about 1 μm to about 500 μm and a biodegradable polyester electrospun outer sheath surrounding the biodegradable polyester core; and a thromboresistant agent coating the biodegradable scaffold, thereby forming a composition that facilitates tissue regeneration. 